About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: firstname.lastname@example.org
April 7, 2014
Here's a good test for whatever news outlets you might be using for biotech information. How are they handling Pfizer's release of palbociclib information from the AACR meeting over the weekend?
Do a news search for the drug's name, and you'll see headline after headline. Many of them include the phrase "Promising Results". And from one standpoint, those words are justified. The drug showed a near-doubling in progression-free survival (PFS) when added to the standard of care, and you'd think that that has to be good. But a first analysis of overall survival (OS) shows no statistically significant improvement.
Now, how can that be? One possibility is that the drug helps hold advanced breast cancer back, until a population of cells breaks through - and when they do, it's a very fast-moving bunch indeed. Pfizer, for its part, is certainly hoping that further collection of data will start to show a real OS effect. They're going to need to - Avastin's provisional approval for breast cancer was based on earlier PFS numbers, which did not hold up when OS data came in. And that approval was revoked, as it should have been. Now, Avastin also had side effect issues, and quality-of-life issues, so these cases aren't directly comparable. But the FDA really wants to see a survival benefit, and that's what a new cancer drug really should offer. "You'll die at the same time, but with fewer tumors, and out more money" is not an appealing sales pitch. This issue has come up several times before, with other drugs, and it will come up again.
You'd think that a PFS effect like palbociclib's should translate into a real survival benefit, and as more data are added, it may well. But it's surely not going to be as impressive as people had hoped for, or it would have been apparent in the data we have. So take a look at the stories you're reading on the drug: if they mention this issue, good. If they just talk about what a promising drug for breast cancer palbociclib is, then that reporter (and that news outlet) is not providing the full story. (Here's one that does).
Update: there is an ongoing Phase III that's more specifically looking at overall survival. Its results will be awaited with great interest. . .
+ TrackBacks (0) | Category: Cancer | Press Coverage
February 25, 2014
Here's a nice look at why you should always think about the source of the financial and business information you read. It details the response to a recent Pfizer press release about palbociclib, a CDK inhibitor that's in late clinical trials.
Someone at The Wall Street Journal wrote that it had "the potential. . .to transform the standard of care for post-menopausal women with ER+ and HER2- advanced breast cancer." Problem is, that phrase was lifted directly out of the press release itself (and sure sounds like it), and you really would hope for better from the WSJ. What we're seeing here is actually Pfizer's own spin on the (as yet unpresented) results of the PALOMA-1 clinical trial. Everything a company says at this point will be couched in terms of "could" and "has the potential" and "we hope", and will come with one of those paragraphs at the end about "forward-looking statements". When it comes to the first statements about clinical trials results, if there are no numbers, there is nothing to talk about.
Paul Raeburn, the Knight Science Journalism blog author who picked up on this, also found that someone at the AP (and others) went for Pfizer's spin, too:
The problem is that this story was covered by business reporters rather than medical reporters, who by and large are too smart to fall for a company's claim about a drug without seeing the evidence presented, reviewed, and debated.
The further problem is that because they are so smart, medical writers mostly declined to cover this story. Which left the business writers out there alone, telling the story the company wanted them to tell.
Well, "medical writer" is a broad term, and believe me, there are some slackjaws in that crowd, too. But point taken - anyone who's been paying attention, or anyone who's willing to spend a few minutes on Google, should have realized that Pfizer is trying to make the case for accelerated approval of palbociclib, especially after the recent failure of dacomitinib and strong competition from Novartis in exactly the same therapeutic space.
Pfizer, of course, is not going to come out and talk about how delighted they are about the Phase II results unless they can back that up with something. I hope that palbociclib bowls people over - a new therapy for breast cancer would be good news. But we haven't seen the data yet, and data are all that will (or should) make pulses race over at the FDA. So I think that the Pfizer press release was worth noting, but stories like the Fierce Biotech one linked in the paragraph above are the way to do it. Put the news in context - don't just reword the press release.
+ TrackBacks (0) | Category: Cancer | Press Coverage
January 30, 2014
This morning I heard reports of formaldehyde being found in Charleston, West Virginia water samples as a result of the recent chemical spill there. My first thought, as a chemist, was "You know, that doesn't make any sense". A closer look confirmed that view, and led me to even more dubious things about this news story. Read on - there's some chemistry for a few paragraphs, and then near the end we get to the eyebrow-raising stuff.
The compound that spilled was (4-methylcyclohexane)methanol, abbreviated as 4-MCHM. That's its structure over there.
For the nonchemists in the audience, here's a chance to show how chemical nomenclature works. Those lines represent bonds between atoms, and if the atom isn't labeled with its own letter, it's a carbon (this compound has one one labeled atom, that O for oxygen). These sorts of carbons take four bonds each, and that means that there are a number of hydrogens bonded to them that aren't shown. You'd add one, two, or three hydrogens as needed to each to take each one up to four bonds.
The six-membered ring in the middle is "cyclohexane" in organic chemistry lingo. You'll note two things coming off it, at opposite ends of the ring. The small branch is a methyl group (one carbon), and the other one is a methyl group subsituted with an alcohol (OH). The one-carbon alcohol compound (CH3OH) is methanol, and the rules of chemical naming say that the "methanol-like" part of this structure takes priority, so it's named as a methanol molecule with a ring stuck to its carbon. And that ring has another methyl group, which means that its position needs to be specified. The ring carbon that has the "methanol" gets numbered as #1 (priority again), so the one with the methyl group, counting over, is #4. So this compound's full name is (4-methylcyclohexane)methanol.
I went into that naming detail because it turns out to be important. This spill, needless to say, was a terrible thing that never should have happened. Dumping a huge load of industrial solvent into a river is a crime in both the legal and moral senses of the word. Early indications are that negligence had a role in the accident, which I can easily believe, and if so, I hope that those responsible are prosecuted, both for justice to be served and as a warning to others. Handling industrial chemicals involves a great deal of responsibility, and as a working chemist it pisses me off to see people doing it so poorly. But this accident, like any news story involving any sort of chemistry, also manages to show how little anyone outside the field understands anything about chemicals at all.
I say that because among the many lawsuits being filed, there are some that show (thanks, Chemjobber!) that the lawyers appear to believe that the chemical spill was a mixture of 4-methylcyclohexane and methanol. Not so. This is a misreading of the name, a mistake that a non-chemist might make because the rest of the English language doesn't usually build up nouns the way organic chemistry does. Chemical nomenclature is way too logical and cut-and-dried to be anything like a natural language; you really can draw a complex compound's structure just by reading its name closely enough. This error is a little like deciding that a hairdryer must be a device made partly out of hair.
I'm not exaggerating. The court filing, by the law firm of Thompson and Barney, says explicitly:
30. The combination chemical 4-MCHM is artificially created by combining methylclyclohexane (sic) with methanol.
31. Two component parts of 4-MCHM are methylcyclohexane and methanol which are both known dangerous and toxic chemicals that can cause latent dread disease such as cancer.
Sure thing, guys, just like the two component parts of dogwood trees are dogs and wood. Chemically, this makes no sense whatsoever. Now, it's reasonable to ask if 4-MCHM can chemically degrade to methanol and 4-methylcyclohexane. Without going into too much detail, the answer is "No". You don't get to break carbon-carbon bonds that way, not without a lot of energy. If you ran the chemical (at high temperature) through some sort of catalytic cracking reactor at an oil refinery, you might be able to get something like that to happen (although I'd expect other things as well, probably all at the same time), but otherwise, no. For the same sorts of reasons, you're not going to be able to get formaldehyde out of this compound, either, not without similar conditions. Air and sunlight and water aren't going to do it, and if bacteria and fungi metabolize it, I'd expect things like (4-methylcyclohexane)carboxaldehyde and (4-methylcyclohexane)carboxylic acid, among others. I would not expect them to break off that single-carbon alcohol as formaldehyde.
So where does all this talk of formaldehyde come from? Well, one way that formaldehyde shows up is from oxidation of methanol, as shown in that reaction (this time I've drawn in all the hydrogens). This is, in fact, one of the reasons that methanol is toxic. In the body, it gets oxidized to formaldehyde, and that gets oxidized right away to formic acid, which shuts down an important enzyme. Exposure to formaldehyde itself is a different problem. It's so reactive that most cancers associated with exposure to it are in the upper respiratory tract; it doesn't get any further.
As that methanol oxidation reaction pathway shows, the body actually has ways of dealing with formaldehyde exposure, up to a point. In fact, it's found at low levels (around 20 to 30 nanograms/milliliter) in things like tomatoes and oranges, so we can assume that these exposure levels are easily handled. I am not aware of any environmental regulations on human exposure to orange juice or freshly cut tomatoes. So how much formaldehyde did Dr. Scott Simonton find in his Charleston water sample? Just over 30 nanograms per milliliter. Slightly above the tomato-juice level (27 ng/mL). For reference, the lowest amount that can be detected is about 6 ng/mL. Update: and the amount of formaldehyde in normal human blood is about 1 microgram/mL, which is over thirty times the levels that Simonton says he found in his water samples. This is produced by normal human metabolism (enzymatic removal of methyl groups and other reactions). Everyone has it. And another update: the amount of formaldehyde in normal human saliva can easily be one thousand times that in Simonton's water samples, especially in people who smoke or have cavities. If you went thousands of miles away from this chemical spill, found an untouched wilderness and had one of its natives spit in a collection vial, you'd find a higher concentration of formaldehyde.
But Simonton is a West Virginia water quality official, is he not? Well, not in this capacity. As this story shows, he is being paid in this matter by the law firm of Thompson and Barney to do water analysis. Yes, that's the same law firm that thinks that 4-MCHM is a mixture with methanol in it. And the water sample that he obtained was from the Vandalia Grille in Charleston, the owners of which are defendants in that Thompson and Barney lawsuit that Chemjobber found.
So let me state my opinion: this is a load of crap. The amounts of formaldehyde that Dr. Simonton states he found are within the range of ozonated drinking water as it is, and just above those of fresh tomato juice. These are levels that have never been shown to be harmful in humans. His statements about cancer and other harm coming to West Virginia residents seem to me to be irresponsible fear-mongering. The sort of irresponsible fear-mongering that someone might do if they're being paid by lawyers who don't understand any chemistry and are interested in whipping up as much panic as they can. Just my freely offered opinions. Do your own research and see what you think.
Update: I see that actual West Virginia public health officials agree.
Another update: I've had people point out that the mixture that spilled may have contained up to 1% methanol. But see this comment for why this probably doesn't have any bearing on the formaldehyde issue. Update, Jan 31: Here's the MSDS for the "crude MHCM" that was spilled. The other main constituent (4-methoxymethylcyclohexane)methanol is also unlikely to produce formaldehyde, for the same reasons given above. The fact remains that the levels reported (and sensationalized) by Dr. Simonton are negligible by any standard.
+ TrackBacks (0) | Category: Chemical News | Current Events | Press Coverage | Toxicology
January 20, 2014
Here's a long article from the Raleigh News and Observer (part one and part two) on the Eaton/Feldheim/Franzen dispute in nanoparticles, which some readers may already be familiar with (I haven't covered it on the blog myself). The articles are clearly driven by Franzen's continued belief that research fraud has been committed, and the paper makes the most of it.
The original 2004 publication in Science claimed that RNA solutions could influence the crystal form of palladium nanoparticles, which opened up the possibility of applying the tools of molecular biology to catalysts and other inorganic chemistry applications. Two more papers in JACS extended this to platinum and looked at in vitro evolutionary experiments. But even by 2005, Franzen's lab (who had been asked to join the collaboration between Eaton and Feldheim, who were now at Colorado and a startup company) was generating disturbing data: the original hexagonal crystals (a very strange and interesting form for palladium) weren't pure palladium at all - on an elemental basis, they were mostly carbon. (Later work showed that they were unstable crystals of (roughly) Pd(dba)3, with solvated THF. And they were produced just as well in the negative control experiments, with no RNA added at all.
N. C. State investigated the matter, and the committee agreed that the results were spurious. But they found Feldheim guilty of sloppy work, rather than fraud, saying he should have checked things out more thoroughly. Franzen continued to feel as if justice hadn't been done, though:
In fall 2009, he spent $1,334 of his own money to hire Mike Tadych, a Raleigh lawyer who specializes in public records law and who has represented The News & Observer. In 2010, the university relented and allowed Franzen into the room where the investigation records were locked away.
Franzen found the lab notebooks, which track experiments and results. As he turned the pages, he recognized that Gugliotti kept a thorough and well-organized record.
“I found an open-and-shut case of research fraud,” Franzen said.
The aqueous solution mentioned in the Science article? The experiments routinely used 50 percent solvent. The experiments only produced the hexagonal crystals when there was a high level of solvent, typically 50 percent or more. It was the solvent creating the hexagonal crystals, not the RNA.
On Page 43 of notebook 3, Franzen found what he called a “smoking gun.”
(Graduate student Lina) Gugliotti had pasted four images of hexagonal crystals, ragged around the edges. The particles were degrading at room temperature. The same degradation was present in other samples, she noted.
The Science paper claimed the RNA-templated crystals were formed in aqueous solution with 5% THF and were stable. NC State apparently offered to revoke Gugliotti's doctorate (and another from the group), but the article says that the chemistry faculty objected, saying that the professors involved should be penalized, not the students. The university isn't commenting, saying that an investigation by the NSF is still ongoing, but Franzen points out that it's been going on for five years now, a delay that has probably set a record. He's published several papers characterizing the palladium "nanocrystals", though, including this recent one with one of Eaton and Feldheim's former collaborators and co-authors. And there the matter stands.
It's interesting that Franzen pursued this all the way to the newspaper (known when I Iived in North Carolina by its traditional nickname of the Nuisance and Disturber). He's clearly upset at having joined what looked like an important and fruitful avenue of research, only to find out - rather quickly - that it was based on sloppy, poorly-characterized results. And I think what really has him furious is that the originators of the idea (Feldheim and Eaton) have tried, all these years, to carry on as if nothing was wrong.
I think, though, that Franzen is having his revenge whether he realizes it or not. It's coming up on ten years now since the original RNA nanocrystal paper. If this work were going to lead somewhere, you'd think that it would have led somewhere by now. But it doesn't seem to be. The whole point of the molecular-biology-meets-materials-science aspect of this idea was that it would allow a wide variety of new materials to be made quickly, and from the looks of things, that just hasn't happened. I'll bet that if you went back and looked up the 2005 grant application for the Keck foundation that Eaton, Feldheim (and at the time, Franzen) wrote up, it would read like an alternate-history science fiction story by now.
+ TrackBacks (0) | Category: Chemical News | Press Coverage | The Dark Side | The Scientific Literature
December 18, 2013
To go along with those nominations for worst press releases of the year, here's a roundup of stinkers in the biomedical field. And they do reek. I got some of these in my in-box as well, and I probably got even more of them than I remember. Sad to say, PR material (or at least the automated list variety) gets a very brief look from me. If there's a personal note to it, that shows that some thought went into the distribution, odds go up. But even then, I get people pitching me on all-natural coconut cure water and the like, apparently laboring under the idea that it's just the think that the readership here would like to hear about. (Those sometimes get "You don't seem to have every actually looked at the site. . ." replies from me).
As for the automated stuff, once in a while I'll actually click through to the release itself, but most of the time, I can tell from the subject line that it's not something that I need to be spending any effort on. My e-mail address has crept on to more and more lists with time, and it's amusing, in a grim way, to see the releasebots sending me automated PR notes on, say, the morning of Thanksgiving and other big news days like that (and no, that didn't appear to be an outlet outside the US in that case - I looked it over at the time, wondering who could be silly enough be sending it). I'll keep an eye out on Christmas and New Year's for the latest news.
+ TrackBacks (0) | Category: Press Coverage
December 17, 2013
In the same spirit as Adam Feuerstein's "Worst Biotech CEO" nominations from the other day, here's Michael Eisen asking what the worst scientific press releases of the year were. Most Overhyped and Most Egregious Failure to Cite Earlier Work are two especially hard categories to win. If you have some examples that particularly got under your skin this year, head on over.
+ TrackBacks (0) | Category: Press Coverage
October 11, 2013
The British press (and to a lesser extent, the US one) was full of reports the other day about some startling breakthrough in Alzheimer's research. We could certainly use one, but is this it? What would an Alzheimer's breakthrough look like, anyway?
Given the complexity of the disease, and the difficulty of extrapolating from its putative animal models, I think that the only way you can be sure that there's been a breakthrough in Alzheimer's is when you see things happening in human clinical trials. Until then, things are interesting, or suggestive, or opening up new possibilities, what have you. But in this disease, breakthroughs happen in humans.
This latest news is nowhere close. That's not to say it's not very interesting - it certainly is, and it doesn't deserve the backlash it'll get from the eye-rolling headlines the press wrote for it. The paper that started all this hype looked at mice infected with a prion disease, which led inexorably to neurodegeneration and death. They seem to have significantly slowed that degenerative cascade (details below), and that really is a significant result. The mechanism behind this, the "unfolded protein response" (UPR) could well be general enough to benefit a number of misfolded-protein diseases, which include Alzheimer's, Parkinson's, and Huntington's, among others. (If you don't have access to the paper, this is a good summary).
The UPR, which is a highly conserved pathway, senses an accumulation of misfolded proteins inside the endoplasmic reticulum. If you want to set it off, just expose the cells you're studying to Brefeldin A; that's its mechanism. The UPR has two main components: a shutdown of translation (and thus further protein synthesis), and an increase in chaperones to try to get the folding pathways back on track. (If neither of these do the trick, things will eventually shunt over to apoptosis, so the UPR can be seen as an attempt to avoid having the apoptotic detonator switch set off too often.
Shutting down translation causes cell cycle arrest, as well it might, and there's a lot of evidence that it's mediated by PERK, the Protein kinase RNA-like Endoplasmic Reticulum Kinase. The team that reported this latest result had previously shown that two different genetic manipulations of this pathway could mediate prion disease in what I think is the exact same animal model. If you missed the wild excited headlines when that one came out, well, you're not alone - I don't remember there being any. Is it that when something comes along that involves treatment with a small molecule, it looks more real? We medicinal chemists should take our compliments where we can get them.
That is the difference between that earlier paper and this new one. It uses a small-molecule PERK inhibitor (GSK2606414), whose discovery and SAR is detailed here. And this pharmacological PERK inhibition recapitulated the siRNA and gain-of-function experiments very well. Treated mice did show some behavioralthis really does look quite solid, and establishes the whole PERK end of the UPR as a very interesting field to work in.
The problem is, getting a PERK inhibitor to perform in humans will not be easy. That GSK inhibitor, unfortunately, has side effects that killed it as a development compound. PERK also seems to be a key component of insulin secretion, and in this latest study, the team did indeed see elevated blood glucose and pronounced weight loss, to the point that that treated mice eventually had to be sacrificed. Frustratingly, PERK inhibition might actually be a target to treat insulin resistance in peripheral tissue, so if you could just keep an inhibitor out of the pancreas, you might be in business. Good luck with that. I can't imagine how you'd do it.
But there may well be other targets in the PERK-driven pathways that are better arranged for us, and that, I'd think, is where the research is going to swing next. This is a very interesting field, with a lot of promise. But those headlines! First of all, prion disease is not exactly a solid model for Alzheimer's or Parkinson's. Since this pathway works all the way back at the stage of protein misfolding, it might be just the thing to uncover the similarities in the clinic, but that remains to be proven in human trials. There are a lot of things that could go wrong, many of which we probably don't even realize yet. And as just detailed above, the specific inhibitor being used here is strictly a tool compound all the way - there's no way it can go into humans, as some of the news stories got around to mentioning in later paragraphs. Figuring out something that can is going to take significant amount of effort, and many years of work. Headlines may be in short supply along the way.
+ TrackBacks (0) | Category: Press Coverage | The Central Nervous System
January 3, 2013
You may have seen some "wonder drug" news stories over the holiday break about compounds targeting p53 - many outlets picked up this New York Times story. The first paragraph probably got them:
For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.
Now, to read that, you might think we're talking mutated p53, which is indeed found in a wide variety of cancers. It's the absolute first thing you think of when you think of a defective protein that's strongly associated with cancer. And everyone has been trying to target it for years and years now, for just that reason, but without too much success. If you know drug development, you might have seen this article and done what I did - immediately read on wondering who the heck it was with a broad-based p53 therapy and how you missed it.
That's when you find, though, that this is p53 and MDM2. MDM2 is one of those Swiss-army-knife proteins that interacts with a list of other important regulatory proteins as long as your leg. (Take a look at the last paragraph of that Wikipedia link and you'll see what I mean). Its relationship with p53 has been the subject of intense research for many years now - it's a negative regulator, binding to p53 and keeping it from initiating its own transcriptional activity. Since a lot of that transcriptional activity is involved with telling a cell to kill itself, that's the sort of thing you'd normally want to have repressed, but the problem in some tumor lines is that MDM2 never gets around to leaving, allowing damaged cancerous cells to carry on regardless.
So, as that newspaper piece says, there have been several long-running efforts to find compounds that will block the p53/MDM2 interaction. The first big splashes in the area were the "Nutlin" compounds, from Roche - named after Nutley, New Jersey, much good did it do the research site in the end. The tangled history of Nutlin-3 in the clinic is worth considering when you think about this field. But for some kinds of cancer, notably many lipsarcomas, this could be an excellent target. That link discusses some results with RG7112, which is one of the drugs that the Times is talking about. Note that the results are, on one level, quite good. This is a tumor type that isn't affected by much, and 14 out of the 20 patients showed stable disease on treatment. But then again, only one patient showed a response where the tumor actually became smaller, and some showed no effect at all. There were also twelve serious adverse events in eight patients. That's not the sort of thing that you might have expected, given the breathless tone of the press coverage. Now, these results are absolutely enough to go on to a larger trial, and if they replicate (safety profile permitting), I'd certainly expect the drug to be approved, and to save the lives of some liposarcoma patients who might otherwise have no options. That's good news.
But is it "the beginning of a new genetic age in cancer research", to quote Gina Kolata's article? I don't see how. The genetic age of cancer has been underway for some time now, and it's been underway in the popular press for even longer. As for this example, there are several types of cancer for which a p53/MDM2 compound could be useful, but liposarcoma is probably the first choice, which is why it's being concentrated on in the clinic. And as far as I know, the number of cancer patients with mutated p53 proteins well outnumber the ones with intact p53 and overexpressed MDM2. These new compounds won't do anything for those people at all.
I sound like such a curmudgeon. But shouldn't there be some level of press coverage in between total silence and Dawn Of A Glorious New Era? I suppose that "Progress Being Made On Tough Drug Target" isn't the sort of hed that makes Page One. But that's the sort of headline that research programs generate.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Press Coverage
December 19, 2012
Well, I've been away from the computer a good part of the day, but I return to find that the author of the NSF press release that I spoke unkindly of has shown up in the comments to that post. I'm going to bring those up here to make sure that his objections get a fair hearing:
I wrote this press release, and I am a bit concerned that instead of discussing the research with myself, or more importantly the researchers, you decide to attack the text.
We presented information based on research that has been underway for some time, at least two years with NSF peer-reviewed support.
Additionally, we were careful to not overstate either the technology or the impact, but to present an illustration of what the technology can do in the limited space that a press release allows.
A journalist is expected to follow the initial reading of the press release with questions for the researchers involved -- not attack the limited text that we provide as an introduction.
In my eleven years at NSF, I have never had someone attack my work -- particularly without first getting their facts straight.
Please contact the researchers to discuss the technology and limit your criticism for those thongs for which you are informed.
Media Officer for Engineering
National Science Foundation
(To add, my supervisor pointed out a stellar typo in my last line.
I'm fear that's where the discussion will go next, but if you do wish to learn more about the actual research you are disparaging, please do contact the researchers to learn more about the technology and the approach.)
Several regular readers have already responded in the comments section to that earlier post, making the point that experienced drug discovery scientists found the language in the press release hard to believe (and reminiscent of overhyped work from the past). Josh Chamot's response is reproduced here:
Thank you for the thoughtful responses. This is exactly the engagement I was hoping for.
First, I agree that hype is never what we want to communicate -- and I appreciate that skepticism is critical to ensuring accuracy and the complete communication of news. However, I do hope many of you will explore the research further so that any skepticism is completely informed.
I want to be clear that I have no intention of misleading the research or pharma communities, nor do I want to give false hope to those who might need any of the treatments that we referenced. Our language was intended to convey that the breakthrough to date is exciting, but clearly more work is needed before this can start producing drugs for patients -- and I believe we stated this.
Through links to additional information (such as the full patent application) and clear contact information for the principal investigator, it is our hope that the primary audience for the press release (reporters) will present a thorough and complete account of the work.
We do not wish to mislead, but we also cannot convey a full news story in press release format. The intent is to serve as an alert, and importantly, an accurate one.
Journalists are the primary audience for the press releases, and our system of information is reliant on their services. To the best of my knowledge, the information we presented on Parabon is accurate and states only results that Parabon has demonstrated and announced in their patent application -- the starting point for a journalist to explore the story further.
As background, the pieces I work on cover research efforts that are originally proposed to NSF in a review process informed by peers in the community. Parabon has received both Phase I and Phase II NSF small business funding, so they had succeeded in that competitive peer review twice.
That setting served as a baseline to inform my office that the research approach was a valid starting point -- however, as with almost all NSF research, this is research at the very earliest stages. I can accept that while I wrote the release to reflect this, I was not successful in conveying this clearly. However, the assertions that data in support of the research effort do not exist are incorrect.
The company first came to our office (public affairs) more than two years ago, and it is only now that the company had enough publicly available information for us to pull together an announcement of the technology and some introduction of how it works.
I have some lessons learned here in how to try to clarify caveats, but I stand by my original assertion that the research is valid and exciting. While I have no way to predict Parabon's ultimate success, I do believe that public discussion of their technique can only prove of value to the broader drug development effort -- including the identification of any obstacles that this, or a similar technique, must overcome.
I think what I'll do now is close off the comments to the previous post and have things move over to this entry, with appropriate pointers, so we don't have two discussion going on at the same time. Now, then. I'm not blaming Mr. Chamot for what went out on the wires, because I strongly suspect that he worked with what he was given. It's the people at Parabon that I'd really like to have a word with. If the press release is an accurate reflection of what they wanted to announce, then we have a problem, and it's not with Jack Chamot.
I realize that a press release is, in theory, supposed to be for the press - for reporters to use as a starting point for a real story. But how many of them do that, versus just rewording the release a bit? There are reporters who could pick up on all the problems, but there are many others who might not. The information in the Parabon release, as it stands, makes little sense to those of us who do drug discovery for a living, seems full of overstated claims, and raises many more questions than it answers. Specialists in the field (as many readers here are) will have an immediate and strong reaction to this sort of thing.
And that's one of the purposes of this blog (and of many others): to bring expertise out into the open, to provide people within some specialized area a chance to talk with each other, and to provide people outside it (anyone at all) a chance to sit in and learn about things they otherwise might never hear discussed. I think that the process that Mr. Chamot has described is an older one: scientists describe a discovery of theirs to some sort of press officer, who puts into some useful and coherent form in order to get the word out to reporters, who then can contact the people involved for more details as they write up their stories for a general readership. That's fine, but these days that whole multistep procedure is subject to disintermediation. And that's what we're seeing right now.
+ TrackBacks (0) | Category: Chemical Biology | Press Coverage
December 18, 2012
I'm having a real problem understanding this press release from the NSF. I've been looking at it for a few days now (it's been sent to me a couple of times in e-mail), and I still can't get a handle on it. And I'm not the only one. I see just this morning that Chemobber is having the same problem. Here, try some. See how you do:
Using a simple "drag-and-drop" computer interface and DNA self-assembly techniques, researchers have developed a new approach for drug development that could drastically reduce the time required to create and test medications. . ."We can now 'print,' molecule by molecule, exactly the compound that we want," says Steven Armentrout, the principal investigator on the NSF grants and co-developer of Parabon's technology. "What differentiates our nanotechnology from others is our ability to rapidly, and precisely, specify the placement of every atom in a compound that we design."
Say what? Surely they don't mean what it sounds like they mean. But they apparently do:
"When designing a therapeutic compound, we combine knowledge of the cell receptors we are targeting or biological pathways we are trying to affect with an understanding of the linking chemistry that defines what is possible to assemble," says Hong Zhong, senior research scientist at Parabon and a collaborator on the grants. "It's a deliberate and methodical engineering process, which is quite different from most other drug development approaches in use today."
OK, enough. I'd love for atom-by-atom nanotech organic synthesis and precisely targeted drug discovery to be a reality, but they aren't. Not yet. The patent application referenced in the press release is a bit more grounded in reality, but not all that much more:
The present invention provides nanostructures that are particularly well suited for delivery of bioactive agents to organs, tissues, and cells of interest in vivo, and for diagnostic purposes. In exemplary embodiments, the nanostructures are complexes of DNA strands having fully defined nucleotide sequences that hybridize to each other in such a way as to provide a pre-designed three dimensional structure with binding sites for targeting molecules and bioactive agents. The nanostructures are of a pre-designed finite length and have a pre-defined three dimensional structure
Ah, and these complexes of DNA strands will survive after in vivo dosing just exactly how? And will be targeted, via that precisely defined structure, just how? And bind to what, exactly, and with what sort of affinities? And are the binding sites on these DNA thingies, or do they bind to other things, anyway? No, this is a mess. And this press release is an irresponsible mishmosh of hype. I'd be glad to hear about some real results with some real new technology, and I'd like to ask the Parabon people to cough some up. I'd be equally glad to feature them on this blog if they can do so, but not if they're going to start talking like they're from the future and come to save us all. Sheesh.
Update: the discussion on this press release features a number of interesting comments. It's now moved over to this post, for reasons explained there. Thanks!
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December 12, 2012
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November 12, 2012
The overhyped nature of stem cell therapies is a topic that's come up here several times. In the latest developments, Pluristem, Inc., is threatening to sue Bloomberg New for their recent report, titled "Girl Dies As Pluristem Sells On Gains With Miracle Cells". Gosh, it's hard to see why the company would take exception to a headline like that, but here's how the piece leads off, in case things weren't clear:
Pluristem Therapeutics Inc.’s (PSTI) stock doubled in Nasdaq trading from May through September, helped by three news releases announcing that patients’ lives had been saved by injections of the company’s experimental stem cells.
After the stock soared on the positive news, two top executives profited by selling shares at the highest price in more than four years as part of a pre-determined program. When the first of those patients, a 7-year-old girl with a bone- marrow disease, died four months after the company said her life had been saved, Pluristem was silent. The company raised $34 million selling shares a week later.
Not so good. But as that link in the first paragraph shows, Pluristem's response has not cleared things up very much. In the same press release in which they demanded a correction from Bloombert, they revealed that another of their three initial patients had also died after four months, which also had not been announced before. The earlier press releases for all three patients are well-stocked with phrases like "medical miracle" and "life-saving". As long as this sort of thing is going on, the stem cell field will continue to have problems.
Update: interestingly, this post seems to have brought a lot of Pluristem's stock market fans flocking. And I mean this in the best possible way, but their appearance here does not inspire confidence.
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September 25, 2012
I've been meaning to write something about the M.D. Anderson announcement of "Moon Shot" programs for cancer therapies. Mostly something about how I'm very glad that they're spending a lot of time and money on this, because there are a lot of good people there, but also about how I truly hate the "Moon Shot" analogy for R&D. As has been said for years, decades. . .the Moon landing was a stupendous feat of applied engineering, but few (if any) new principles had to be discovered along the way. Attacking cancer, though, is like trying to engineer a moon landing when you're not sure where the moon is. Or what it's made out of. Or what the various kinds of rocket fuel might be.
And the whole thing was made much, much worse by CNN, who proclaimed "Cure for Cancer Close" as some sort of exclusive scoop. That ridiculous situation is summed up well here. As it turns out, this was a combination of the M.D. Anderson press release and one of those "We could save more people just by applying our existing knowledge more thoroughly" angles. All in all, a really shoddy performance, which I hope had people both at CNN and M. D. Anderson burying their heads in their hands.
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May 23, 2012
Several readers sent along a link to this Radio 4 program ("The End of Drug Disocvery") from the BBC on drug discovery. From what I've heard, it's a very good overview of the current state of the field for people outside it, and gets across just how difficult it's been to find good drug candidates.
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February 13, 2012
Nobelist Roald Hoffman has directly taken on a topic that many chemists find painful: why aren't more chemistry Nobel prizes given, to, well. . .chemists?
". . .the last decade has been especially unkind to "pure" chemists, asa only four of ten Nobel awards could be classified as rewarding work comfortably ensconced in chemistry departments around the world. And five of the last ten awards have had a definite biological tinge to them.
I know that I speak from a privileged position, but I would urge my fellow chemists not to be upset."
He goes on to argue that the Nobel committee is actually pursuing a larger definition of chemistry than many chemists are, and that we should take it and run with it. Hoffmann says that the split between chemistry and biochemistry, back earlier in the 20th century, was a mistake. (And I think he's saying that if we don't watch out, we're going to make the same mistake again, all in the name of keeping the discipline pure).
We're going to run into the same problem over and over again. What if someone discovers some sort of modified graphene that's useful for mimicking photosynthesis, and possibly turning ambient carbon dioxide into a useful chemical feedstock? What if nanotechnology really does start to get off the ground, or another breakthrough is made towards room-temperature superconductors, this time containing organic molecules? What would a leap forward in battery technology be, if not chemistry? Or schemes to modify secreted proteins or antibodies to make them do useful things no one has ever seen? Are we going to tell everyone "No, no. Those are wonderful, those are great discoveries. But they're not chemistry. Chemistry is this stuff over here, that we complain about not getting prizes for".
+ TrackBacks (0) | Category: General Scientific News | Press Coverage | Who Discovers and Why
November 21, 2011
In response to the press coverage on the FDA's Avastin decision on Friday, a reader forwarded a revised and extended version of the New York TImes article that appeared soon afterwards. Here are some excerpts, which I think get across the thinking of many medicinal chemists and drug researchers. His contributions are bolded for emphasis, although it's not all that hard to see where the original ends and his revisions start.
"The commissioner of the Food and Drug Administration on Friday revoked the approval of the drug Avastin as a treatment for breast cancer, ruling in an emotional issue that pitted the hopes of some desperate patients against the statistics of clinical trials, two things that should never be compared, because that would be stupid.
The commissioner, Dr. Margaret A. Hamburg, said that the drug was not helping breast cancer patients to live longer or control their tumors, but did expose them to potentially serious side effects such as severe high blood pressure and hemorrhaging, making her decision very easy.
. . .The F.D.A. “recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use.” Also, they shouldn’t take drugs that don’t work, so we thought that is was important that they stop eating 88 thousand dollar magic beans, and instead use drugs and medical procedures that work.
. . .Avastin will remain on the market as a treatment for other types of cancers, including forms of cancer that it actually treats, so doctors can use it off-label for breast cancer if they hate science. But some insurers might no longer pay for the drug, which would put it out of reach of many women because it costs about $88,000 a year.
pressure came from the other direction as well the outcome was certain once the statistical analysis was done, so this could have been a much shorter article. The administration had pledged to make scientific decisions on the basis of science, which seems like a pretty good idea as well. That made it difficult for Dr. Hamburg to go against the pharmaceutical lobby, and easy to accept the conclusions of the F.D.A.’s own staff and the strong recommendations of the outside experts on its advisory committee.
. . .An initial clinical trial showed that Avastin, when combined with the drug (paclitaxel), delayed appeared to delay the progression of disease by about five and
a half months, compared to use of paclitaxel alone. However, the women who received
Avastin in the study did not live significantly longer and they suffered more side effects. As an example, high doses of sodium cyanide completely stops the progression of disease almost immediately and permanently, though women who receive this treatment don’t live as long and suffer more serious side effects from the control group.
. . .Many breast cancer specialists say that Avastin does appear to work very well for some patients, but that the effect gets drowned in a clinical trial that looks at overall results. Some doctors and patient advocates argued the drug should remain available for that reason. Representatives from large sugar companies also noted that their drug, placebo, works very well for some patients, but that effect is usually gets drowned in a clinical trial that looks at overall results. The FDA has yet to approve placebo for the treatment of breast cancer."
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November 15, 2011
Are stem cells overhyped? That topic has come up around here several times. But there have been headlines and more headlines, and breathless reports of advances, some of which might be working out, and many of which are never heard from again. (This review, just out today, attempts to separate reality from hype).
Today brings a bit of disturbing news. Geron, a company long associated with stem cell research, the company that started the first US trial of embryonic stem cell therapy, has announced that they're exiting the field. Now, a lot of of this is sheer finances. They have a couple of oncology drugs in the clinic, and they need all the cash they have to try to get them through. But still, you wonder - if their stem cell trial had been going really well, wouldn't the company have gotten a lot more favorable publicity and opportunities for financing by announcing that? As things stand, we don't know anything about the results at all; Geron is looking for someone to take over the whole program.
As it happens, there's another stem-cell report today, from a study in the Lancet of work that was just presented at the AHA. This one involves injecting heart attack patients with cultured doses of their own cardiac stem cells, and it does seem to have helped. It's a good result, done in a well-controlled study, and could lead to something very useful. But we still have to see if the gains continue, what the side effects might be, whether there's any advantage to doing this over other cell-based therapies, and so on. That'll take a while, although this looks to be on the right track. But the headlines, as usual, are way out in front of what's really happening.
No, I continue to think that stem cells are a very worthy subject of research. But years, quite a few years, are going to be needed before treatments using them can become a reality. Oh, and billions of dollars, too - let's not forget that. . .
+ TrackBacks (0) | Category: Biological News | Business and Markets | Cancer | Cardiovascular Disease | Press Coverage
October 13, 2011
There's been an interesting dispute playing out over the last few weeks about science reporting. Here's a summary, but I'll give one as well: it all got started with David Kroll, aka "Abel Pharmboy" of the Terra Sigillata blog (and another, Take as Directed). On that latter site, he'd written about science articles in the popular press, and the line between having a scientist fact-check a piece about their work, and giving that same scientist editorial power.
Ananyo Bhattacharya, editor of Nature, then wrote a column in the Guardian on the topic, where he warned that there was indeed a line that could be crossed:
". . .It's a trap I've fallen into in the past. Either a scientist you have talked to insists on checking the final version of the story with the threat of "withdrawing" their contribution to your piece (it feels churlish to point out that they have already agreed to speak to you on the record) or, an hour or two before deadline you're struck by a creeping fear that somewhere, something is dreadfully wrong and so you call on one or more of your friendly sources to read it over. . .Part of the problem is that many scientists interpret the journalist's request that they "check the facts and your quotes only please" rather loosely. Some are under the impression that because their lab carried out the work being reported, they have some sort of ownership of the subsequent coverage. This is not the case."
But then the Guardian ran a strongly dissenting view from three neuroscientists from Cardiff University. Their take was that peer review is the secret sauce, and that accuracy is the greater good:
Science is different for four reasons, one categorical, three of degree. The categorical difference is the process of peer review. Every research article in a reputable scientific journal has been through a process in which between two and five independent experts (normally anonymous) have made extensive comments. . .
Overall, since press credibility relies on both accuracy and independence, and since the question of allowing sources to check articles (or parts of them) raises a tension between these pillars, the burning question is: where should the balance be struck?
We believe that public trust in science, and in science reporting, is harmed far more by inaccuracy than by non-independence. Contrary to Bhattacharya's claim that "the reader is not a scientist's first concern," public understanding is our overriding concern when communicating with journalists.
As it happens, these very authors had recently been scorched by sensationalized reporting of their work in the British tabloids. Now, I agree that for an accurate picture of any given scientific project, I'd sooner bring in a paleolithic Amazonian shaman for his take before turning to the Sun or the Daily Mail. But I still have to disagree that accuracy is the absolute trump card - I'm willing to accept some moronic misrepresentations in order to keep things more honest, and I think that honesty is best served when things don't run quite so smoothly. We should all keep each other on our toes - the alternative is an invitation to logrolling and groupthink, which can do more harm, in the long run, than sensationalism.
And it should go without saying that the Cardiff researchers' appeal to peer review just doesn't stand up. Five minutes over on Retraction Watch will show you what peer review is capable of letting through. And there are plenty of good scientists who will tell you about what peer review is capable of keeping out of the journals as well. No, it's a very imperfect system. I'm not saying that I can think of a better one at the moment, but appealing to it as if it's one of the glories of civilization is silly. (I see that I'm not alone in reacting this way).
And a bit more than silly - it's arrogant as well. This is what we as scientists have to look out for, the de haut en bas attitude where we come in and explain all the complicated stuff to the peasants. People can detect that, you know, and when they do they get suspicious (and rightly so, at times) that we have something to hide. No, speaking as a scientist, and a blogger, and (mostly on the opinion side) perhaps a journalist as well, I think we're better off with a system where everyone keeps an eye on everyone else. If we get too cozy and consensus-driven, we're going to invite real trouble.
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September 20, 2011
I wrote last year about Foldit, a collaborative effort to work on protein structure problems that's been structured as an open-access game. Now the team is back with another report on how the project is going, and it's interesting stuff. The headlines have generally taken the "Computer Gamers Solve Incredible Protein Problem That Baffled Scientists!" line, but that's not exactly the full story.
The Foldit collaboration participated in the latest iteration of a regular protein-structure prediction challenge, CASP9. And their results varied - in the category of proteins with known structural homologs, for example, they didn't perform all that well. The players, it turned out, sort of over-worked the structures, and made a lot of unnecessary changes to the peripheral parts of the proteins. Another category took on proteins that have no identified structural homologs, a much harder problem. But that had its problems, too, which illustrate both the difficulties of the Foldit approach and protein modeling in general:
For prediction problems for which there were no identifiable homologous protein structures—the CASP9 Free Modeling category—Foldit players were given the five Rosetta Server CASP9 submissions (which were publicly available to other prediction groups) as starting points, along with the Alignment Tool. . .In this Free Modeling category, some of the shortcomings of the Foldit predictions became clear. The main problem was a lack of diversity in the conformational space explored by Foldit players because the starting models were already minimized with the same Rosetta energy function used by Foldit. This made it very difficult for Foldit players to get out of these local minima, and the only way for the players to improve their Foldit scores was to make very small changes ('tunneling' to the nearest local minimum) to the starting structures. However, this tunneling did lead to one of the most spectacular successes in the CASP9 experiment.
. . .the Rosetta Server, which carried out a large-scale search for the lowest-energy structure using computing power from Rosetta@home volunteers, produced a remarkably accurate model . . . However, the server ranked this model fourth out of the five submissions. The Foldit Void Crushers team correctly selected this near-native model and further improved it by accurately moving the terminal helix, producing the best model for this target of any group and one of the best overall predictions at CASP9 . . . Thus, in a situation where one model out of several is in a near-native conformation, Foldit players can recognize it and improve it to become the best model. Unfortunately for the other Free Modeling targets, there were no similarly outstanding Rosetta Server starting models, so Foldit players simply tunneled to the nearest incorrect local minima.
In the Refinement challenge, where participants take a minimized structure and try to improve its accuracy, the Foldit players had similar problems with starting from structures that had already been minimized by the same tools that they were using. Every change tended to make things look worse. The team improved their performance by reposting one of the structures as a new challenge, this time keeping the parts that were known with confidence to be near-native, while more or less randomizing the other parts to give a greater diversity to the starting points.
And those really are some of the key problems in this work. There are an awful lot of energy minima out there, and which ones you can get to depend crucially on where you start looking. In order to get to a completely different manifold of protein structures, even ones with much better energies, you may well have to go through a zone where you look like you're ruining everything. (And most of the time, you probably are ruining everything - there's no way to know if there's a safe haven on the other side or not).
But this paper also reports the results that are getting the headlines, a structure for the Mason-Pfizer monkey retroviral protease. This is an interesting protein, because although it crystallizes readily (in several different forms), and although the structures of other retroviral proteases are known, no one has been able to solve this one from the available X-ray data. The Foldit players, however, came up with several proposals that fit the data well enough for the structure to finally fall out of the diffraction data. It does have some odd features in its protein loops, different enough from the other proteases for no one to have hit on it before.
And that really is an accomplishment, and the way it was solved (with different players building on the results of others, competing to get the best optimization scores) really is the way the Foldit is supposed to work. Their less impressive performance on the CASP9 problems, though, shows that the same protein prediction difficulties apply to Foldit players as apply to the rest of the modeling field. This isn't a magic technique, and Foldit gamers are not going to rampage through the structural biology world solving all the extant problems any time soon. But it's nothing to sneeze at, either.
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July 29, 2011
I've been meaning to comment on this article from the Wall Street Journal - the authors take a look at the drug approval numbers so far this year, and speculate that the industry is turning around.
Well, put me in the "not so fast" category. And I have plenty of company there. Neither Bruce Booth (from the venture capital end), John LaMattina (ex-Pfizer R&D head) nor Matthew Herper at Forbes are buying it either.
One of the biggest problems with the WSJ thesis is that most of these drugs have been in development for longer than the authors seem to think. Bruce Booth's post goes over this in detail, and he's surely correct that these drugs were basically all born in the 1990s. Nothing that's changed in the research labs in the last 5 to 10 years is likely to have significantly affected their course; we're going to have to wait several more years to see any effects. (And even then it's unlikely that we're going to get any unambiguous signals; there are too many variables in play). That, as many people have pointed out over the years, is one of the trickiest parts about drug R&D: the timelines are so long and complex that it's very hard to assign cause and effect to any big changes that you make. If your car only responds to the brake pedal and steering wheel a half hour after you touch them, how can you tell if that fancy new GPS you bought is doing you any good?
+ TrackBacks (0) | Category: Drug Development | Drug Industry History | Press Coverage | Regulatory Affairs
July 21, 2011
I wanted to call attention to another blog roundtable, on several subjects related to how nonchemists see us and our business. The first post (at ScienceGeist) is on chemical safety (industrial chemicals = bad?). Day 2, at ChemJobber, is on whether the general public has any good idea of not only what chemists do (we work with chemicals, right?) but why and how we do it. Day 3, at ChemBark, takes things to a practical level, showing how lack of understanding can confuse people about energy policy (does growing corn to make ethanol make any sense?) And Day 4, at The Bunsen Boerner, is on a topic I've been known to go off on myself, the use (and mostly the misuse) of the word "organic".
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June 29, 2011
. . .you either have to go to the specialty press, or (sometimes) to the last couple of paragraphs of a mainstream article. For several years now, it's been hard to think of any medical field that's been more relentlessly overhyped than stem cell therapy (a worst-case example was its appearance in the 2004 elections, courtesy of the ever-reliable John Edwards?).
FiercePharma has a good short look at an article in Time that is much more well-balanced than most, but still has some of the usual problems. And don't get me wrong - I think that stem cells are an exciting area of research, an excellent thing to be investigating, and could quite possibly lead to some wonderful results. But not next week. And not without a few billion dollars, most likely. Anyone who tells you otherwise is, to my mind, to be regarded with suspicion.
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June 24, 2011
Here's a op-ed from Josh Bloom (ex-Wyeth) in the New York Post that will resonate with a lot of people out there. A sample:
The folks at Scientific American have launched "1,000 Scientists in 1,000 Days" -- a program to bring together scientists, teachers and students to improve America's "dismal" showing among wealthy countries (27th out of 29) in graduating college students with degrees in science or engineering. I'm sure they mean well -- but, at least as it applies to the field of chemistry, "1,000 Unemployed Scientists Living With Their Parents at Age 35 While Working at the Gap" would be a better name.
He goes on to tell the readership what it's been like in drug discovery over the last few years, and it'll probably be news to many of them. I'm glad that people are getting the word out!
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June 15, 2011
I was going to take a shot at this article myself, a piece in The Atlantic called "The Triumph of New Age Medicine". But Matthew Herper at Forbes has done the job for me. The original article advances the thesis that modern medicine isn't doing much for chronic diseases, which is why people are turning to acupuncture, et al. Says Herper:
. . .that’s all horse microbiome. Let’s take those one by one. Saying we’re not making strides against heart disease and cancer is just, well, wrong. Look at the below chart of mortality from both, courtesy of the Centers for Disease Control and Prevention. Notice something? They’re both going down. . .Yes, the battle against heart disease and cancer is slow, grinding trench warfare, but that’s because these our diseases written by evolution into our genetic code. And we’re still winning.
He goes on to demolish one of the article's other sweeping claims - that alternative medicine focuses on prevention, but mainstream medicine doesn't. And he's got an interesting reason (which may have occurred to you before) for why most "alternative" therapies have such ardent fans. Hint: there really is a secret ingredient, which has been gradually removed from a lot of modern medical practice. . .
+ TrackBacks (0) | Category: Press Coverage | Snake Oil
June 9, 2011
There have been quite a few headlines over the last few days like this one: "A New Drug Makes Hearts Repair Themselves". Unfortunately, that's not quite true. Not yet.
It's this paper in Nature that's getting the attention, and it is a very interesting one. The authors have identified a population of progenitor cells in the adult heart that can be induced to turn into fully differentiated myocytes after an infarction. In fewer syllables, and reasonably accurately: stem cells, already in the heart, can be made to repair it after a heart attack. And that's getting closer to that headline I was just complaining about - so what's the gap between the two?
Well, there are several rather huge factors. One of them is that the way that these cells were stimulated into action was by treatment with thymosin beta-4, which is a potent regulator of cardiac cells and blood vessel development. Tβ4 is not quite a drug yet, although RegeneRx is giving it a shot. There have been some phamacokinetic studies in animals and other preliminary work, and I wish them every good fortune. But it's got a ways to go.
Second, this study treated the animals with Tβ4 for seven days before inducing the cardiac injury. That's perfectly reasonable for a proof-of-concept study like this one, but it's not the real-world therapeutic option that you'd imagine from the press coverage. As one correspondent put it to me in an e-mail, "if you’re a mouse, and you know that later on this week you’re going to have an MI, then this is the treatment for you". That might be unfair to the original authors, who are working their way up carefully through some very tricky biology, but it's not unfair at all to the people who write headlines like the one I quoted above.
No, this is very interesting stuff, but it's quite a ways from being ready to help any of us out. This is where such therapies start, though, and we can only hope that something makes it through this time. The authors themselves know the score:
". . .The induced differentiation of the progenitor pool described into cardiomyocytes by Tβ4 is at present an inefficient process relative to the activated progenitor population as a whole. Consequently, the search is on via chemical and genetic screens to identify efficacious small molecules and other trophic factors to underpin optimal progenitor activation and replacement of destroyed myocardium.
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June 7, 2011
I found this article in The American Scholar via Arts and Letters Daily, entitled "Flacking for Big Pharma". As you might have possibly guessed from the title, it's a broadside against the advertising practices of the drug industry, and particularly against its interactions with physicians and the medical journals.
And I'll say up front that the piece is not, in fact, completely wrong. It's probably not even mostly wrong. There really are big problems in these areas, such as too-aggressive promotion, minimization of side effects, too many payments to "key opinion leaders", too many studies that don't see the light of day, and so on. And these things really do lower the respect that people have for the drug industry - assuming, by this point, that there's much respect left. But overall, this article is sort of a summary version of Marcia Angell's book, for people who would like to hate the drug industry but find themselves pressed for time. And as such, it manages to get some important things wrong in the process of getting some things right.
For example, it makes much of subgroup analysis of clinical trials, but as a way for drug companies to pull the wool over readers' eyes. I wonder how much this really happens, though, since overzealous data mining of a trial that wasn't powered to generate such conclusion is (you'd think) a well-known pitfall by now. Perhaps not, though. But the example given in the article is BiDil:
BiDil proponents published studies that supported their claim of a racially mediated genetic anomaly that was addressed by BiDil, making it an ideal drug for blacks but not for whites.. . .
NitroMed won FDA approval of a new trial that included only 1,050 black subjects, with no white subjects to provide comparison data. Furthermore, BiDil was not tested alone, but only in concert with heart medications that are already known to work, such as diuretics, beta-blockers, and angiotensin-converting enzyme (or ACE) inhibitors. The published results of the trial were heralded as a success when subjects taking the drug combinations that included BiDil enjoyed 43 percent fewer heart-failure deaths.
. . .excluding whites was a medically illogical but financially strategic move because it eliminated the possibility that the drug would test well in whites, thereby robbing NitroMed of its already thin rationale for calling BiDil a black drug. The “black” label was crucial, because BiDil’s patent covering use in all ethnic groups expired in 2007, but the patent for blacks only allows NitroMed to profit from it until 2020. BiDil is a case study in research methodology “flaws” that mask strategies calculated to make a dodgy drug look good on paper, for profit.
But this doesn't appear to be correct. First off, as the article itself mentioned earlier, the BiDil combination was originally tested (twice) in racially mixed (in fact, I believe, mostly white) trial groups. Secondly, the 1,050-patient trial in black patients was done with other therapies because to do otherwise would be unethical (see below). And what you wouldn't realize by reading all this is the BiDil, in fact, was a failure. No one's making piles of profits on BiDil until 2020, especially not NitroMed. You wouldn't even know that NitroMed itself gave up trying to sell BiDil three years ago, and that the company itself was acquired (for a whopping 80 cents a share) in 2009.
Now, about those placebo-controlled trials. This article makes much of a British Medical Journal satire from 2003 on how to make a drug look good. But it's confused:
A placebo, such as a sham or “sugar” pill, has no active ingredient, and, although placebos may evoke some poorly understood medical benefits, called the “placebo effect,” they are weak: medications tend to outperform placebos. Placebo studies are not ethical when a treatment already exists for a disorder, because it means that some in the study go untreated. However, if you care only that your new drug shines in print, testing against placebo is the way to go.
Well, which is it? We can't, in fact, run placebo-controlled trials just to "shine in print" when there's a standard of care, you know. You can only do that when there's no standard of care at all. And in those cases, what exactly should we use as a comparison? Using nothing at all (no pills, nothing) would, in fact, make our drugs look even better than they are, because of that placebo effect. This is a specious objection.
And when there's a standard of care that a new drug will be added to (as was the case with BiDil), then you actually do have to run it with those therapies in place, at least when you get to Phase III. The FDA (and the medical community) want to know how your drug is going to perform in the real world, and if patients out in that real world are taking other medications, well, you can't pretend that they aren't.
In another section, the article makes much of the Merck/Elsevier affair, where Elsevier's "Excerpta Medica" division set up some not-really-journals in Australia (blogged about here). That was, in fact, disgraceful (as I said at the time), but disgraceful apparently isn't enough:
. . .Elsevier, the Dutch publisher of both The Lancet and Gray’s Anatomy, sullied its pristine reputation by publishing an entire sham medical journal devoted solely to promoting Merck products. Elsevier publishes 2,000 scientific journals and 20,000 book-length works, but its Australasian Journal of Bone and Joint Medicine, which looks just like a medical journal, and was described as such, was not a peer-reviewed medical journal but rather a collection of reprinted articles that Merck paid Elsevier to publish. At least some of the articles were ghostwritten, and all lavished unalloyed praise on Merck drugs, such as its troubled painkiller Vioxx. There was no disclosure of Merck’s sponsorship. Librarian and analyst Jonathan Rochkind found five similar mock journals, also paid for by Merck and touted as genuine. The ersatz journals are still being printed and circulated, according to Rochkind, and 50 more Elsevier journals appear to be Big Pharma advertisements passed off as medical publications. Rochkind’s forensic librarianship has exposed the all-but-inaccessible queen of medical publishing as a high-priced call girl.
Fifty journals? Really? As far as I can tell, that figure comes from this analysis at the time, and seems to be mostly nonce publications, one-off conference proceedings, and the like. There is a whole list of "Australasian Journal of So-and-Sos", which would be the same reprint advertorials as the other Excerpta Medica stuff, but do these still exist? (Did all of them on the list, in fact, ever actually publish anything?)
You'd get the impression that Elsevier is (or was, until Big Pharma came along) an absolute shining pinnacle of the medical establishment - but, with apologies to the people I know who work there, that is unfortunately not the case. They're big, and they're very far from the worst scientific publishers out there, but some of their titles are, in fact, not adding much to the total of human knowledge. Nor has the conduct of their marketing department always been above reproach. But no, this has to be built up to look even worse than it is.
The irritating thing is that there's plenty to criticize about this industry without misrepresenting reality. But does that sell?
+ TrackBacks (0) | Category: Press Coverage | The Dark Side | The Scientific Literature | Why Everyone Loves Us
March 9, 2011
What's going on over at Slate, anyway? So far this week we've been talking about that Timothy Noah article over there publicizing the bizarre Light and Warburton estimate for drug development. Now one of their house blogs erupts with a geyser of idiocy about the looming patent cliff in the industry:
So this sudden terrible problem has been obvious and on schedule for at least 10 years.
It honestly is that simple and that stupid. The pharmaceutical industry turned all its energy toward wringing as much money as possible out of the drugs it already had, and quit making any sort of plans that would lead to having a new (and, you know: medically useful) batch of drugs under patent in the future, when the patents on the old batch expired.
Now the pharmaceutical companies are laying off tens of thousands of workers because they are worried about their financial future, because although they are officially in the business of producing and selling drugs, they stopped producing drugs.
It goes on in that vein; in fact, it gets even more stupid. And the point isn't that someone wrote something like this, so much as that this reflects, I fear, what a lot of other people think. Writing this blog has exposed me to a lot of smart, interesting people, which is something I really enjoy. But it's also exposed me to a lot of troglodytes who have no idea of what they're talking about. And here we have another one. Unfortunately, if enough people believe something idiotic, those beliefs can have consequences.
Now, we can argue about pharma strategy, which we do all the time around here. Where to spend the time and money, which programs to push and which to walk away from - everyone's got their own opinions. But if the line you're pushing is that drug companies just haven't been doing any research at all for the last ten or twenty years. . .well, then you're a moron. On the evidence of this column, Slate's Tom Scocca is one, at best, and his piece is a waste of electrons.
For one thing, there actually have been a few drugs introduced over the last ten years or so. Not as many as we'd like, or as many as we were planning on, but still. And then there are the failures. I mean, I say a lot of nasty things about Pfizer here, for example, but we can list off the big drug projects that they've had die on them over the last few years. Same for Merck, for Novartis, for BMS and AZ and for everyone else.
Honestly, I really think that we should make a bigger deal out of clinical failures in this industry, so that people realize that (1) we're always trying to do something, (2) it doesn't always work, and (3) it costs a godawful amount of money. As it is now, no one outside of the industry really notices or remembers when the giant multi-year research programs go down in expensive flames. And that leaves the door open for knuckle-dragging stuff as quoted above, and for the fools who believe it.
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February 15, 2011
Update: call off the dogs! I've heard from a colleague of Dr. Pepys, who strongly believes that this was a tongue-in-cheek remark. He assures me that Pepys has been around the clinical development block a number of times in the field of amyloidosis, which is a hard enough area to give anyone a good idea of what discovering a useful therapy is really like.
This would not be unheard of - both for a newspaper story to quote a flippant remark out of context, and for the tone of such a remark to be completely lost once it appeared on paper. After looking the situation over, I think that's just what's happened here. It's a sad thing, though, that a remark like this is close enough to some real opinions that it could be taken as read. . .
From the Financial Times:
GlaxoSmithKline aims to sign up 10 academic “superstars” this year for long-term partnerships to help develop medicines more effectively and cheaply. . .
The move comes as the UK pharma group cuts back on costly but unproductive early-stage in-house research and attempts to shift from investment in fixed assets towards more flexible partnerships with external developers.
GSK has recently finalised its first such contract with Professor Mark Pepys, head of medicine at the Royal Free and University College Medical School in London, designed to develop a treatment for a rare form of amyloidosis. (Glaxo senior VP Patrick) Vallance said he planned to sign 10 such deals this year. . .
“It’s a wonderful idea,” said Prof Pepys. “We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else."
Were I working for GSK, I would be very, very excited. Finally, a clear statement of what the company thinks of its own employees. The Sirtris deal (and others) have hinted at the contempt under the surface, but it's good to get it out into the open. Isn't it?
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November 8, 2010
I noticed this editorial in Nature Structural and Molecular Biology, on getting scientific results out to the public. It's worth reading, but not in the way that they think. It starts out reasonably well:
As members of the research community, we know we can't rely on the popular media to correct the misperceptions the public might harbor about science-related issues. According to a 2009 Pew Research Center survey of Americans, carried out in conjunction with the American Association for the Advancement of Science (AAAS), 76% of scientists feel the media do not adequately distinguish between substantial findings and those that are unfounded. Although it would be easy to say that the public “just doesn't get it,” the burden of passing along the understanding and implications of contemporary science falls squarely on the shoulders of those actively engaged in funding, publishing and carrying out research.
That's been said before, as the editorial itself notes, but it's no less true for all that. And the advice that follows is sound, if still rather boring: when you talk to non-scientists, try to gauge how much they know about the subject (without offending people), lay off the acronyms and jargon, look for helpful (and accurate) analogies, and so on. All fine.
But then the piece floats off into the mist - or, more accurately, floats off into about the year 1976.How do we get the word out to the public? Well, we need public officials on our side, it says. But take heart! "Globally, several world leaders have voiced support for increasing the promotion of science in their countries", and that should cheer anyone up on a rainy Monday morning. How anyone was able to type that line without burying their head in their hands is beyond me.
There's more. "It is important that we engage the public where they are", says the editorial, and I can't argue with that one, since trying to engage 'em where they ain't is unlikely to prove fruitful. And here comes the rain of musty pillows again: "A growing number of organizations and institutions are seeking to do this through several different approaches", says the next line. You can just hear the (unsigned) writer thinking "Dang it, what's the word count supposed to be on this thing again?" Whoever it is goes on to point out that Sloan-Kettering hosts an annual seminar for just that purpose.
It's only in the last couple of lines that anything useful gets said. Because if we agree that the public should know more about science, and if we've decided that we should go where they are to realize that, then the two places I'm sure that they might be found are online and watching TV, and maybe both at the same time. Just under the wire, the editorial manages to mention that there are these things called web sites, and even (quickly and quietly) suggests that people start their own.
I like that one, understandably. And although it's not like I get millions of readers here, I still get a lot more than I ever thought (between 350,000 and 400,000 page views a month these days). Many are people who are already in the sciences, but I continue to hear from readers with no particular science background at all, which makes me very happy indeed.
But how much science do I really get across? Well, it's not like I'm trying to teach people to do drug discovery, since it's unfortunately not well suited to trying at home. What I'd like for all science outreach activities to do, though, is get across what science really is, what research is like, and broadly how it works. There are so many things that people outside the field don't necessarily get to experience or realize: how much time we spend chasing ideas that weren't right, for one. How much time we spend making sure that we made what we thought we made, or that we did what we thought we did, and trying to nail down how much we can believe what we think that we know. How little that is, in many cases, and how we're always getting surprised even in the areas that looked well-understood.
Real scientific research is quite bizarre by the standards of many other occupations, and I don't think that people get to understand that. (I might add that the ways in which science gets compressed for dramatic effect tends to obscure all these things - TV and movie scientists are always so sure of themselves, and get their rock-solid results so quickly). So rather than start off by trying to teach everyone lots of details, I'd rather that more people understood what the whole effort is like. . .
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August 25, 2010
Emily Yoffe at Slate has a very accurate piece up on just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases. The contrast with the hopes of patients - and the hype often surrounding the initial discoveries - is painful.
And we're back to that optimism/realism tightrope. On the one hand, I don't see any reason why we shouldn't be able - eventually - to stop such conditions in their tracks, or to keep them from starting in the first place. (Reversing the damage once it's done, though, is much more of a stretch, to me). But on the other hand - sheesh, we really, really have a lot to learn about these things. The likelihood of any one discovery being the key breakthrough is small - nonzero, but small. So in the long term, I'm an optimist, but in the short term, well. . .every little bit helps, and most of the bits are going to be little.
That's not the sort of news you want to give to someone suffering from these conditions, of course. That desire for encouraging news, along with plenty of other good intentions (and a few not-so-good-ones) leads to the cycles of hype that we've seen over and over. Stem cell research is a perfect example. There really are huge possibilities there, extraordinary ones. But our level of ignorance is also extraordinary. And to go out and make claims that we're going to be able to cure X and reverse Y soon, based on our present knowledge, is just plain irresponsible.
But plenty of people do just that - politicians, headline writers, and others. And then people who only know what they see in the news wonder where things went wrong, and how come these wonderful cures haven't arrived yet. It all makes explaining the real situation that much harder.
It's not like the real situation is even all that terrible. As I said above, I really do think that these diseases - and many others - are eventually going to be treatable. No one likes that word "eventually", though.
+ TrackBacks (0) | Category: Press Coverage | The Central Nervous System
August 13, 2010
I'm of two minds on this New York Times article on Alzheimer's research. It details some recent progress on biomarkers for the disease, and that work does look to be useful. A lot of people have proposed diagnostics and markers for Alzheimer's and its progression over the years, but none of them have really panned out. If these do, that's something we haven't had before.
But my first problem is something we were talking about here the other day. Biomarkers are not necessarily going to help you in drug development, not unless they're very well validated indeed. We really do need them in Alzheimer's research, because the disease progression is so slow. And this effort is really the only way to find such things - a good-sized patient sample, followed over many years. But unfortunately, 800 people (divided out into different patient populations) may or may not be enough, statistically. We're now going to have to take the potential assays and markers that this work has brought up and see how well they work on larger populations - that's the only way that they'll be solid enough to commit a clinical trial to them. Both the companies developing drugs and the regulatory agencies will have to see convincing numbers.
That general biomarker problem is something we really can't do anything about; the only cures are time, effort, money, and statistical power. So it's not a problem peculiar to Alzheimer's (although that's a tough proving ground), or to this collaborative effort. But now we come to the collaborative effort part. . .overall, I think that these sorts of things are good. (This gets back to the discussions about open-source drug discovery we've been having here). Bigger problems need sheer manpower, and smaller ones can always benefit from other sets of eyes on them.
The way that this Alzheimer's work puts all the data out into the open actually helps with that latter effect. All sorts of people can dig through the data set, try out their hypotheses, and see what they get. But I think it's important to realize that this is where the benefit comes from. What I don't want is for people to come away thinking that the answer is that we need One Big Centralized Effort to solve these things.
My problem with the OBCE model, if I can give it an acronym, is that it tends to cut back on the number of ideas and hypotheses advanced. Big teams under one management structure don't tend to work out well when they're split up all over the place. There's managerial (and psychological) pressure, from all directions, to get everyone on the same idea, to really get in and push that one forward with all the resources. This is why I worry about all the consolidation in the drug industry: fewer different approaches get an airing when it's all under the roof of one big company.
So this Alzheimer's work is just the sort of collaboration I can admire: working on a big problem, sharing the data, and leaving things open so that everyone with an idea can have a crack at it. I just hope that people don't get the wrong idea.
+ TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials | Press Coverage | Who Discovers and Why
July 9, 2010
John Lechleiter of Eli Lilly has an op-ed in today's Wall Street Journal on innovation in the US. Needless to say, he's worried:
A recent study ranked the U.S. sixth among the top 40 industrialized nations in innovative competitiveness, but 40th out of 40 in "the rate of change in innovation capacity" over the past decade. The ranking, published last year by the Information Technology and Innovation Foundation, measured what countries are doing—in higher education, investment in research and development, corporate tax rates, and more—to become more innovative in the future. The U.S. ranked dead last.
He goes on to say that we need a climate that appreciates new technology (which I certainly think we have), the financial system to support it (which is where he makes the case for favorable tax treatment), and the pe